Tissue eosinophilia is a feature of a number of pathological conditions such as asthma, rhinitis, eczema and parasitic infections (see Bousquet, J. et al., N. Eng. J. Med. 323:1033–39 (1990) and Kay, A. B. and Corrigan, C. J., Br. Med. Bull. 48:51–64 (1992)). In asthma, eosinophil accumulation and activation are associated with damage to bronchial epithelium and hyperresponsiveness to constrictor mediators. Chemokines such as RANTES, eotaxin and MCP-3 are known to activate eosinophils (see Baggiolini, M. and Dahinden, C. A., Immunol. Today, 15:127–33 (1994), Rot, A. M. et al., J. Exp. Med. 176:1489–95 (1992) and Ponath, P. D. et al., J. Clin. Invest., 97(3):604–12 (1996)). However, unlike RANTES and MCP-3 which also induce the migration of other leukocyte cell types, eotaxin is selectively chemotactic for eosinophils (see Griffith-Johnson, D. A. et al., Biochem. Biophy. Res. Commun. 197:1167 (1993), and Jose, P. J. et al., Biochem. Biophy. Res. Commun. 207:788 (1994)). Specific eosinophil accumulation has been observed at the site of administration of eotaxin, whether by intradermal or intraperitoneal injection or aerosol inhalation (see Griffith-Johnson, D. A. et al., supra; Jose, P. J. et al., supra; Rothenberg, M. E. et al., J. Exp. Med. 181:1211 (1995), and Ponath, P. D., supra).
Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related disorders, including bronchial asthma (R. P. Schleimer et al., Am. Rev. Respir. Dis., 141:559 (1990)). The glucocorticoids are believed to inhibit IL-5 and IL-3 mediated eosinophil survival in these diseases. However, prolonged use of glucocorticoids can lead to side effects in patients such as glaucoma, osteoporosis, and growth retardation (see Hanania, N. A. et al., J. Allergy and Clin. Immunol., 96:571–79 (1995) and Saha, M. T. et al., Acta Paediatrica, 86(2):138–42 (1997)). It is therefore desirable to have an alternative means of treating eosinophil-related diseases without incurring these undesirable side effects.
Recently, the CCR-3 receptor was identified as a major chemokine receptor that eosinophils use for their response to eotaxin, RANTES and MCP-3. When transfected into a murine pre-beta lymphoma line, CCR-3 bound eotaxin, RANTES and MCP-3 conferred chemotactic responses on these cells to eotaxin, RANTES and MCP-3 (see Ponath, P. D. et al., J. Exp. Med., 183:2437–48 (1996)). The CCR-3 receptor is expressed on the surface of eosinophils, T-cells (subtype Th-2), basophils and mast cells and is highly selective for eotaxin. Studies have shown that pretreatment of eosinophils with an anti-CCR-3 mAb completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 (see Heath, H. et al., J. Clin. Invest., 99(2):178–84 (1997)). U.S. Pat. Nos. 6,140,344 and 6,166,015 issued to Applicant herein and EP application EP903349, published Mar. 24, 1999 disclose CCR-3 antagonists that inhibit eosinophilic recruitment by chemokine such as eotaxin.